Leishmaniasis is a neglected tropical disease, vectored by sand flies and caused by the protozoan parasites of the Leishmania genus, that affects 12 million people globally. Drosophila models for the study of host-Leishmania interactions have been developed, and it is proposed to exploit the unique and powerful genetic tools available in this model system to discover novel and conserved factors required for the phagocytosis and/or intracellular survival of Leishmania parasites. In fact, CD36-like scavenger receptors have been identified as critical components of anti-parasitic defenses in Drosophila. Extending this discovery to mice, CD36 deficiency was found to cause enlarged and persistent foot pad lesions following Leishmania infection, and ex vivo CD36-deficient macrophages present markedly reduced parasitophorous vacuoles. These phenotypes demonstrate that the CD36 scavenger receptor plays a crucial role in L. amazonensis infection, which will be further characterized in Aim 1. Using a Drosophila cellbased model, a genome-wide RNAi screen to identify genes involved in the phagocytosis of L.amazonensis amastigotes was also performed. This screen identified 52 highly conserved genes required for the phagocytosis of Leishmania, but not involved in phagocytosis of bacteria. One candidate is the transmembrane protein Draper, a scavenger receptor best known for its role in recognizing and clearing apoptotic or damaged cells, suggesting it also functions in parasite recognition (Aim 2). It is not yet known if the other candidates are involved in parasite recognition, intracellular trafficking or other aspecs of parasite phagocytosis/invasion. In order to focus on the most promising candidates for study in mammals, Aim 3 will characterize the function of these other factors in the phagocytosis of Leishmania in mammalian macrophage cell lines.